The invention concerns implant materials on the basis of hydraulic cements in the form of one or several pastes, suspensions or dispersions containing mineral and/or organic and/or organo-mineral solids that upon combination or reaction with an aqueous liquid react in a cement-like curing reaction to a solid material as well as their use as technical, medical-engineering and/or pharmaceutical products, in particular as bone cements, bone replacement materials, bone adhesives, tooth filling materials and implantable carriers for active ingredients.
Mineral reactive systems have been in use for a long time in the form of various cements, plasters, etc. Typically, they are comprised of mineral powders that are mixed with water. These mixtures cure within minutes up to days and reach their final composition often only after days to months. The curing reaction is usually comprised of a dissolution of water-soluble powder components and subsequent precipitation of a more stable or less soluble phase or salt form, or in a recrystallization of meta-stable powder components to a modification that is more thermodynamically stable under the application conditions. Often, two or several water-soluble powder components react to a hardly soluble substance.
Mineral cements are seldomly used in pure form but contain usually large proportions of mineral or organic fillers and/or are reinforced by addition of organic, mineral or metallic fibers (or other reinforcement elements).
The prevalence of mineral reactive systems has greatly increased in the last decades and this despite the increase and spread of alternative materials such as metals, ceramics and plastic materials. An important reason for this is the great application-related diversification of the relatively minimal number of principally different reactive systems. This diversification is expressed primarily in the application-related preformulation of reactive components with fillers, reinforcement elements, substances that affect the flowability, adhesion, curing kinetics, frost resistance etc. Examples are, in addition to the classic Portland cement and gypsum, formulations that are already mixed with a suitable type and quantity of sand in accordance with their use as screed or plastering coat. Mixtures with different polymers (dissolved and/or dispersed) have opened further fields of application for the mineral reactive systems (for example, thin-bed adhesives for tile, injectable dowel compounds) that would not be realizable with purely mineral starting materials and have therefore created significant added value in industry.
In medicine (medical engineering) mineral cements have also been used more and more for some years now. First, they have been used as dental filling materials (for example, root fillings) and since approximately 1990 also as filling and reinforcement materials for bone defects in oral and maxillofacial surgery (OMF surgery) as well as orthopedics. Primarily in the medical field the use of mineral reactive systems is still at its beginnings, primarily because only a very limited number of substances is acceptable for use in the body and because very stringent requirements are placed on the products with respect to purity and quality. With respect to the starting materials, moreover many substances are not obtainable in the required quality and must therefore be specifically produced for these applications.
An additional hurdle for expanding the use of mineral reactive systems in medicine and technology is the typical admixture of powder and liquid. This is in any case of a complex nature and the quality of the result is based on the ability and care of the user. In case of medical applications, it is all the more difficult that the mineral cements that have been introduced so far in this field react very sensitively with respect to deviations of the powder/liquid ratio and the clinical users—in contrast to technical applications (e.g. in construction)—up to now have had little training and little experience (the existing long-term experience with polymer-based reactive systems—PMMA bone cement—is moreover rather impairing because the mineral reactive systems behave completely differently) in the preparation of the mineral reactive systems.
The attempts in regard to simplification of powder-liquid mixtures have not yet been successful. In medical technology primarily different mixing systems have been developed that reduce the variability caused by the user and increase the handling comfort for the user.
EP1520562 A2 discloses a device for mixing and dispensing liquid and powdery materials for medical use with a mixing cylinder and a perforated mixing piston that is axially and rotatably movable within the mixing cylinder by means of an actuating rod, with an axially movable dispensing piston and with a closable dispensing piston at the mixing cylinder. This patent application shows in an exemplary manner the apparatus-based expenditure that is proposed by a manufacturer of bone cements as a solution for the problems of powder/liquid mixture under surgery conditions. Basically, however this proposal (like that of many others) does not solve the problem but only compensates to a certain degree by increased apparatus-based expenditure. Moreover, in practice it has been found that despite complex apparatus structure, these devices in no way provide satisfactory results without intensive training and practice. An apparatus-based solution therefore can be eliminated.
U.S. 2004/244651 A1 discloses calcium phosphate cement composition of at least two reactive components in liquid or pasty form that as a carrier liquid contain exclusively water and/or aqueous solutions. The compositions of the exemplary mentioned cements are in line with conventional calcium phosphate cements but contain additional mineral components in order to stabilize the thus produced pastes. Any expert in the field of calcium phosphate cements will question whether one of the mentioned exemplary formulations of the described composition will have an extended shelf life. For the so-called meta-stable calcium phosphates—tetracalcium phosphate (TTCP), β-tricalcium phosphate (β-TCP), and α-tricalcium phosphate (α-TCP)—it holds true in any case that they are stable only under practically anhydrous conditions. All manufacturers of such cements therefore stress the need for manufacturing conditions and packaging that minimize access of water (or moisture in the air) to the cement powder.
S. Takagi, S. Hirayama, A. Sugawara and L. C. Chow disclose in their publication PREMIXED CALCIUM PHOSPHATE CEMENT PASTES (Sixth World Biomaterials Congress Transactions; 2000) experiments in regard to mixing different calcium phosphate cements with glycerine as a carrier liquid. After introduction of these preparations into aqueous solutions they react to solid materials that however have relatively minimal strength values and exhibit very long curing times. Glycerine is moreover a very hygroscopic substance that has the tendency to absorb water so that the shelf life is limited. This problem applies in principle to all liquids that are miscible in the chemical sense with water that, moreover, in most cases can be made anhydrous only with great expenditure. The same group of authors disclose in a newer publication (Premixed rapid setting calcium phosphate composites for bone repair; Carey, Xu, Simson, Takagi, Chow in Biomaterials 26 (2005) 5002-5014) formulations that have been further developed and that employ also water-soluble carrier liquids and compensate some of the aforementioned disadvantages by modifications of the composition. The disadvantages of potentially minimal shelf life and the lack of universal applicability onto the various reactive organo-mineral reactive systems remains however untouched thereby.
WO 2002/062721 A1 and WO 2004/093734 A2 disclose a premixed calcium phosphate cement paste of a mixture of glycerine as a carrier liquid and a calcium phosphate with different additives that, in contact with aqueous solutions, cure to a solid material. This formulation is supposed to reduce the aforementioned disadvantages of the cement paste of calcium phosphates and glycerine by addition of acids and gel forming agents and in particular lead to shorter curing times and improved paste cohesion. The principal disadvantage of cement pastes that are based on water-soluble carrier liquids (see above) is however not eliminated thereby. The additives are able to compensate them only partially. A universally applicable method and composition for producing a paste-based (bone) cement with extended shelf life is not possible therewith. U.S. Pat. No. 6,642,285 B1 discloses a calcium phosphate cement composition that contains a hydrophobic liquid. Accordingly, first calcium phosphate powder is mixed with the appropriate aqueous mixing solutions and the resulting pastes are mixed then with oils in order to obtain, with addition of emulsifying agents and as a function of the stirring intensity, emulsions that after curing of the calcium phosphate paste result in a porous cement structure. Apparently, the thus obtained porous shaped bodies and granules have only minimal strengths so that a subsequent thermal treatment is required for their fortification. These compositions and the described methods for manufacture are unsuitable as cement-based preparations because, in addition to minimal mechanical strengths, they are even more difficult with respect to manufacture than the powder/liquid mixtures themselves.
WO 01/76649 A1 discloses admixture of hydrophobic liquid, in particular oil or fat, to powdery components of mineral bone cements with the goal to improve the rheologic properties of the bone cement and to facilitate the admixture of pharmacological active ingredients. In particular, the hydrophobic liquid is supposed to improve the release of pharmaceutical active ingredients (for example, vitamin E) in the body. As a result of the admixture of maximally 10% (and preferred 2-6%) of the hydrophobic liquid according to WO 01/76649 A1 a powder is obtained that before injection must be carefully and efficiently mixed.